Mechanisms of DNA-binding specificity and functional gene regulation by transcription factors

Smith, Ngaio C.; Matthews, Jacqueline M.

doi:10.1016/j.sbi.2016.05.006

Cited by 61 publications

(46 citation statements)

References 60 publications

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“…[50] In addition to the genomic co-localization data, the absence of IL1A response to dioxin in TCF21 knockdown, and our studies investigating the phasing of binding site placement also suggests some form of direct or indirect molecular interaction. The striking difference between functional annotations for the two categories of steric relationship are consistent with different functional interactions between AHR–ARNT and TCF21 in the context of DNA binding.…”

Section: Discussionmentioning

confidence: 80%

TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells

et al. 2017

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Both environmental factors and genetic loci have been associated with coronary artery disease (CAD), however gene-gene and gene-environment interactions that might identify molecular mechanisms of risk are not easily studied by human genetic approaches. We have previously identified the transcription factor TCF21 as the causal CAD gene at 6q23.2 and characterized its downstream transcriptional network that is enriched for CAD GWAS genes. Here we investigate the hypothesis that TCF21 interacts with a downstream target gene, the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates the cellular response to environmental contaminants, including dioxin and polycyclic aromatic hydrocarbons (e.g., tobacco smoke). Perturbation of TCF21 expression in human coronary artery smooth muscle cells (HCASMC) revealed that TCF21 promotes expression of AHR, its heterodimerization partner ARNT, and cooperates with these factors to upregulate a number of inflammatory downstream disease related genes including IL1A, MMP1, and CYP1A1. TCF21 was shown to bind in AHR, ARNT and downstream target gene loci, and co-localization was noted for AHR-ARNT and TCF21 binding sites genome-wide in regions of HCASMC open chromatin. These regions of co-localization were found to be enriched for GWAS signals associated with cardio-metabolic as well as chronic inflammatory disease phenotypes. Finally, we show that similar to TCF21, AHR gene expression is increased in atherosclerotic lesions in mice in vivo using laser capture microdissection, and AHR protein is localized in human carotid atherosclerotic lesions where it is associated with protein kinases with a critical role in innate immune response. These data suggest that TCF21 can cooperate with AHR to activate an inflammatory gene expression program that is exacerbated by environmental stimuli, and may contribute to the overall risk for CAD.

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Section: Discussionmentioning

confidence: 80%

TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells

et al. 2017

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“…Nevertheless, it is tempting to speculate that cooperative binding of more than one TF regulates expression of developmental genes. Gene regulation through protein‐protein and protein‐DNA networks has previously been described for eukaryotic TFs (Smith and Matthews, ) and may explain why only small shifts in PRO1‐dependent gene expression were observed in the qRT‐PCR for some of the genes investigated. However, esdC expression is drastically increased in GFP‐PRO1_OE, indicating that esdC expression directly depends on PRO1.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor PRO1 targets genes encoding conserved components of fungal developmental signaling pathways

Steffens

Becker

Krevet

et al. 2016

Molecular Microbiology

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SummaryThe filamentous fungus Sordaria macrospora is a model system to study multicellular development during fruiting body formation. Previously, we demonstrated that this major process in the sexual life cycle is controlled by the Zn(II) 2 Cys 6 zinc cluster transcription factor PRO1. Here, we further investigated the genome-wide regulatory network controlled by PRO1 by employing chromatin immunoprecipitation combined with next-generation sequencing (ChIP-seq) to identify binding sites for PRO1. We identified several target regions that occur in the promoter regions of genes encoding components of diverse signaling pathways. Furthermore, we identified a conserved DNA-binding motif that is bound specifically by PRO1 in vitro. In addition, PRO1 controls in vivo the expression of a DsRed reporter gene under the control of the esdC target gene promoter. Our ChIP-seq data suggest that PRO1 also controls target genes previously shown to be involved in regulating the pathways controlling cell wall integrity, NADPH oxidase and pheromone signaling. Our data point to PRO1 acting as a master regulator of genes for signaling components that comprise a developmental cascade controlling fruiting body formation.

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“…47,48 Many of these proteins, for example the lac repressor, use one conformation to carry out nonspecific DNA binding during scanning and switch to a different conformation upon specific target recognition. 49 While further experiments will be required to test these possibilities for the decapping complex, regulation of mRNA decapping may be controlled by protein-protein interactions that manipulate the conformational transitions of Dcp2 to promote or inhibit different steps in the catalytic cycle.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of mRNA-cap recognition by Dcp1–Dcp2

Mugridge

Ziemniak

Jemielity

et al. 2016

Nat Struct Mol Biol

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Removal of the 5′ cap on mRNA by the decapping enzyme Dcp2 is a critical step in 5′-to-3′ mRNA decay. Understanding the structural basis of Dcp2 activity has been a significant challenge because Dcp2 is dynamic, with weak affinity for cap substrate. Here we present a 2.6-Å-resolution crystal structure of a heterotrimer of fission yeast Dcp2, its essential activator Dcp1, and the human NMD cofactor PNRC2, in complex with a tight-binding cap analog. Cap binding is accompanied by a conformational change of Dcp2 to form a composite nucleotide binding site using conserved residues on the catalytic and regulatory domains. Kinetic analysis of PNRC2 reveals a conserved short linear motif enhances both substrate affinity and the catalytic step of decapping. These findings explain why Dcp2 requires a conformational change for efficient catalysis and reveals that coactivators can promote RNA binding and the catalytic step of decapping, possibly through different conformational states.

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Mechanisms of DNA-binding specificity and functional gene regulation by transcription factors

Cited by 61 publications

References 60 publications

TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells

TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells

Transcription factor PRO1 targets genes encoding conserved components of fungal developmental signaling pathways

Structural basis of mRNA-cap recognition by Dcp1–Dcp2

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